Yes, she said 'complementary techniques' which, at this point, in the context of where the research community is, appears to simply mean antibody tests. I'm sure she had other tests in mind, some of which, I guess, require being able to find the virus in ME/CFS blood samples and grow it, which it appears no one else has been able to do (although I haven't seen all the Workshop results)

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I think by complementary techniques she means the variety of tests they ran in the Science paper, most of which were serology-based (but not antibody detection tests), and one of which was an infectivity experiment. Alter stated that only the WPI paper had been so comprehensive; the point is that this multiple test approach improves one's chance of finding a mysterious virus, whereas PCR only is risky due to genetic variation and unknown subtleties relating to sample collection and processing.

I would disagree here as well. Yes, of course, antibodies are being tested and they are discussed for but the main focus now is not on uncovering why the antibody results are off - it's on why the PCR results are off. I think the research community feels that they need to get the PCR questions resolved and they are reluctant to move forward until they do so.

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I actually wasn't disagreeing with you about the emphasis on getting to the bottom of the PCR discrepancy, as you will note from my last post, but only with your assessment (if I understood you correctly) that Mikovits' comments about doing more than PCR in any study fell on deaf ears... they didn't (Frank Ruscetti made sure of that!). However, I don't personally think they should focus exclusively on PCR, as serology can provide valuable information to further support their efforts in figuring out what is going wrong (for instance, if they can all find antibodies even when PCR is negative for one or more labs). And actually I don't think they are being exclusive; all parties seem to be using or working on different kinds of serological assays at the same time.

I would disagree. Several points were made by Dr. Coffin and others. Patients may not agree, but that doesn't invalidate them.

1. Clinical trials control for variables in a way that case studies often do not. There is more to be learned about a population as a whole in a clinical trial than by individual results. As Coffin put it, "off label doesn't help everyone, just the individual."

2. Coffin did back the possibility of small scale studies to find biomarkers of anti-virals

3. If scientists do not yet have a handle on how these specific viruses behave, and they do not yet, then it is difficult to precisely target the behavior in order to modify it in a clinically meaningful way.

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Hi Kelly,

I think people on this thread were arguing for clinical trials (at least I know I was, anyway!), not small, uncontrolled case studies. The difference between Coffin's approach and Mikovits' is the choice of parameter. Coffin wants to wait til we can accurately monitor viral load, while Mikovits wants to monitor other parameters for which there is already evidence of correlations with symptomology in ME/CFS. A great many clinical trials have been done in a great variety of diseases with no known causative agent; the parameters in these cases are usually clinical ones like those Mikovits suggested, and have sometimes been as simple as functional improvement -- usually with some form of objective measure, of course. [Among these are the deplorable clinical trials of antidepressants in CFS and FM patients which have used no 'objective' measures beyond highly questionable psychometric assessments (at most); obviously antiretrovirals have higher potential levels of toxicity, but antidepressants have their own safety issues.] It is worth pointing out, too, that viral load may not correlate with ME/CFS symptoms or observable pathology at all, as Coffin himself noted in another context.

For example, Mindi Kitei on CFS Central noted that Dr. Klimas is also being cautionary. According to Dr. Klimas, antivirals can have a bad effect on cell mitochondria which is a problem in CFS. Other studies have shown that some anti-virals can amplify an autoimmune effect.

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All true (for antiretrovirals that is, not for antivirals in general), but irrelevant to the question of holding off on antiretroviral trials until a qPCR assay is developed.

In general, patients think about situations as they apply to themselves. That is not necessarily how scientists view things in general nor should they. Both points of view are necessary.

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Having been both, I am intimately familiar with that difference of perspective! And Dr. Mikovits is a scientist too, and we are discussing her argument, not a patient's. Also, as evidenced by the PNAS commentary, there is not (at this point) a scientific or clinical consensus opposing clinical trials until a viral load assay is developed.

I should add that, in my experience, patients who support the idea of clinical trials of antiretrovirals are by no means predominantly ignorant of the scientific perspective or medical concerns. Longtime ME/CFS patients are all too familiar with the spider web metaphor, as we have experienced these effects over and over, through a series of alleged 'magic bullets'. It is wise to be extremely cautious with ARV's, and it looks to me like that caution is common on CFS patient forums.

So it looks like we have another task: get research and attention on fixing the disease, not only on the presence and activity of a virus. How do we know that knocking down this particular virus would cure the disease? Even if it was the original cause, reducing the already vanishingly small amount in blood might not get us out of here.

You can find and remove a box of matches, but that action won't put out a fire.

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Excellent analogy. Other studies of anti-virals in CFS patients do note that they are most successful in the first five years of the disease so it is quite possible that disease stage matters.

Which begs the question, when does damage become permanent? What can and cannot be reversed?

Clinicians have argued for years that CFS can be diagnosed after a month not six months saying that the sooner the trigger is mitigated the more likely clinicians will be able to prevent more serious and possibly permanent damage.

But, the six month time period is what makes it "chronic" and may have been chosen by people vested in the hypothesis that the symptoms of CFS are common to everyone - people with CFS just complain more.

I think people on this thread were arguing for clinical trials (at least I know I was, anyway!), not small, uncontrolled case studies. The difference between Coffin's approach and Mikovits' is the choice of parameter. Coffin wants to wait til we can accurately monitor viral load, while Mikovits wants to monitor other parameters for which there is already evidence of correlations with symptomology in ME/CFS. A great many clinical trials have been done in a great variety of diseases with no known causative agent; the parameters in these cases are usually clinical ones like those Mikovits suggested, and have sometimes been as simple as functional improvement -- usually with some form of objective measure, of course. [Among these are the deplorable clinical trials of antidepressants in CFS and FM patients which have used no 'objective' measures beyond highly questionable psychometric assessments (at most); obviously antiretrovirals have higher potential levels of toxicity, but antidepressants have their own safety issues.] It is worth pointing out, too, that viral load may not correlate with ME/CFS symptoms or observable pathology at all, as Coffin himself noted in another context.

All true (for antiretrovirals that is, not for antivirals in general), but irrelevant to the question of holding off on antiretroviral trials until a qPCR assay is developed.

Having been both, I am intimately familiar with that difference of perspective! And Dr. Mikovits is a scientist too, and we are discussing her argument, not a patient's. Also, as evidenced by the PNAS commentary, there is not (at this point) a scientific or clinical consensus opposing clinical trials until a viral load assay is developed.

I should add that, in my experience, patients who support the idea of clinical trials of antiretrovirals are by no means predominantly ignorant of the scientific perspective or medical concerns. Longtime ME/CFS patients are all too familiar with the spider web metaphor, as we have experienced these effects over and over, through a series of alleged 'magic bullets'. It is wise to be extremely cautious with ARV's, and it looks to me like that caution is common on CFS patient forums.[/QUOTE]

I do stand by my comments, but I believe you have some very good points also.

On Sept. 10 pictureofhealth suggested we read Dr. Cheney's comments on the workshop, which were sent to Rich Van K with permission to re-post. Thank you for doing so, pictureofhealth! For those who are reading this blog somewhere other than the PR website, or who do not know where to find the thread, I have copied and pasted Rich Van K's post with Dr. Cheney's comments:

Default Dr. Cheney comments on the XMRV workshop

Hi, all.

Dr. Paul Cheney has given me permission to post the following comments that he has written about the XMRV workshop on Sept. 7-8, 2010, which he attended. Please don't address questions to me about his comments, because I do not want to keep bugging him. I hope you will understand.

Best regards,

Rich

"I attended and was a poster presenter at the recently completed XMRV conference at the NIH. It was fascinating and I took perhaps 30 pages of notes. The bio-political undertones were also intense but I have to say that the presentations of XMRV association with CFS (4 presentations) were much stronger than the presentations of negative XMRV associations with CFS (4 presentations). They were stronger specifically because of the multiple methods they employed and not just PCR. Very interesting in this regard were comments by the head of the blood working group at the NIH who is trying to determine the cause of the discrepancy. He hinted strongly that it is the way blood is collected and processed for nucleic acids and not the detection methods for XMRV itself that divides the two groups. In an NIH blood group sponsored study, a group comparison study with both camps represented detect successfully, in a blinded fashion, XMRV spiked buffer in varying concentrations but they nevertheless divide into two camps when clinical blood samples are taken and processed for XMRV nucleic acids. Using only PCR, one camp sees ~80% positive in CFS and one camp sees 0% positive in CFS There is no one in between and no middle ground between the two groups which was striking and noted by Joe B. who was also in attendance. There is no evidence by mouse mitochondrial DNA probes, that any of the positive associations were contaminated. However, one of the negative association speakers found non-human mouse virus MLV contamination perhaps localized to heparin tubes used for blood collection. Heparin is often produced in China where mice are common as pets. When the contamination was cleared, she found no association of XMRV with CFS.

"I also wanted to share some other highlights of the conference Among them, a very interesting presentation was made by a group connected to Abbott Labs that infected male and female Macaques (monkeys closely related to man) with human XMRV to see what happens and where the virus ends up or concentrates itself.

"Within a few weeks, the virus was largely cleared from blood where it was initially injected in high concentration. Even antibody response was lost over time (months) as the infection was largely removed from the blood and virus did not appear to persist in the blood. Apparently, there was not enough viral antigen to keep antibody levels high or persistent. However, the virus was found more or less in every organ, at least initially, and thought to be carried around the body in T-cells and B-cells during the active phase of infection. This is consistent with the ubiquitous nature of the Xpr1 receptor used by the virus to gain access to almost all cells of the body. Organs where the virus was initially most concentrated appeared to be lymphoid organs such as the spleen, liver and mesenteric nodes of the GI track and in sex organs and in particular the epithelium of the prostate gland where it was highly concentrated at first and then the infected cells later apoptosed and infection disappeared from the epithelium and then the virus was more likely to be seen in the interstitial cells in the stroma or matrix of the prostate, especially the fibroblasts which may be one reservoir in all the various organs that are initially infected. The virus was also found in the epithelium of the cervix in the female macaque. Over time, the infections of various organs tended to be cleared by either immune mechanisms but especially by restriction enzyme systems present in almost all human cells that hypermutate the virus so it cannot persist as a competent infectious agent. Indeed, mutated viral strains are almost always found in CFS cases by both Judy Mikovits at WPI and Frank Ruscetti at NCI. Sometimes this makes the virus incompetent as an infectious agent and sometimes has no effect on infectiousness.

"Very interesting is that another cell that appears to be a reservoir of XMRV other then fibroblasts within tissue stroma are tissue macrophages The pulmonary alveolar macrophages were absolutely loaded with XMRV virus and other tissue macrophages could also be a potential reservoir in other tissues as well, especially in the GI tract, sex organs and sinuses. Tissue macrophage reservoirs would be analogous with HIV as well. It would seem that bronchial secretions, nasal secretions and sex organ secretions as well as feces and urine are well positioned to help the virus to spread itself to other macaques, especially if activated.

"As for activation of more or less low level or quiescent but persistent infectious virus, there seem to be several mechanisms. The virus has both a glucocorticoid response element (GRE) and an androgen response element (ARE) in its promotor region. It also has binding regions for NK Kappa B proteins in its response elements. In any organ with high levels of local androgenic stimulation such as the prostate and perhaps during puberty, the virus could activate. No mention was made of the effect of the predominant female sex hormones but estrogen is the equivalent androgen-like hormone in females. As for the GRE in the promotor region, severe stress will activate the virus or the use of glucocortocoid hormones and perhaps any precursor steroid hormone such as pregnenolone. As for the NF Kappa B sites, any strong immune response with an associated cytokine storm would also be a strong stimulant and such stimulation certainly occurs in the bronchial tree which is frequently stimulated with antigen, especially during allergy season.

"Perhaps most interesting of all was what happened with the injection of a bolus of foreign peptides into macaques that had apparently completely cleared the virus from blood. There was a huge reactivation of infectious virus in the blood proving that latent but persistent virus is just below the surface and that XMRV infection cannot be completely cleared from all reservoir sites. The peptide injection mimics an acute infection (? borrelia or the flu), an immunization or even acute mold exposure.

"The effect of XMRV infection over time was not studied in the macaque but a similar gammaretrovirus called Feline Leukemia virus (FeLV) has been well studied in cats for decades. I will in another post describe a most interesting talk at this conference by a veterinarian on the life history of infection by a gammaretrovirus in cats."

"Is this like a dog chasing its tail?" I remember how sluggish politics made any new proposal when I was teaching at a small highly politicized art college.

Besides our laborious scientific tradition tucked inside unwieldy bureaucritized institutes, I am supposing that politics is happening. A lot of people hung their hats, adamantly, on CFS as psychopathology. They need some time to save face and resettle their egos. This doesn't happen quickly, especially when they are persons who can't be dropped out of the system cleanly, maybe not ever.

I'm fairly certain that's also why Mikovitz didn't directly answer the question about anti-viral trials. That she came back around at the end was about as "in your face" as she could get. And I'd suppose, too, that this kind of "almost" directness of hers is one reason that she isn't more generously accepted in the "general scene". I'm glad of it, of course. It's her position and she's playing it well.

It is frustrating to see it all take longer because of BS, but on the other hand, there is no way they can get away with shenanigans anymore, so we can sit back and enjoy the show (whatever of it they'll let us see). I'll bet there'll be a few last attempts to derail/drag, but, hey, the train is finally rumbling down it's tracks.

"Perhaps most interesting of all was what happened with the injection of a bolus of foreign peptides into macaques that had apparently completely cleared the virus from blood. There was a huge reactivation of infectious virus in the blood proving that latent but persistent virus is just below the surface and that XMRV infection cannot be completely cleared from all reservoir sites. The peptide injection mimics an acute infection (? borrelia or the flu), an immunization or even acute mold exposure.

"The effect of XMRV infection over time was not studied in the macaque but a similar gammaretrovirus called Feline Leukemia virus (FeLV) has been well studied in cats for decades. I will in another post describe a most interesting talk at this conference by a veterinarian on the life history of infection by a gammaretrovirus in cats."

Paul Cheney, M.D.

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Frustrating. Does it seem to anyone else that all this is not headed in a helpful direction...? Less hope in discovering XMRV as a key player in CFS, and more of the same politicized discussion of it as just another pathogen (EBV, HHV6, Lyme, etc.) in the mix that might cause that bewildering CFS in people who must have susceptible genes and like to whine? Can we look forward to XMRV becoming like Lyme--politics and no medical consensus after decades?

If discussion of the monkeys if pointless (disability level was not measured in them, their ability to "clear" the virus and possibly enjoy remission seems dissimilar to most PWC, who just decline forever), and there's more useful information in the cats with FeLV, then please DISCUSS THE CATS WITH FeLV.

Big difference with monkey study.... Over a short period of time after initial infection. They showed the infections reactivated due to stress, hormones, puberty, and flu like infections. Study wasn't long enough to show when the viral load was large enough to tip the "health scale" to permanent infection. When I got first hit with CFS took 5 yrs to get back to 80%, and severe relapses every 5 years or so and each one worse than last... 21 yrs & counting. But who knows how long a person has the virus until they get CFS.... isn't it an average of 10 years for someone with HIV to show AIDS? All sites of viral harbor are areas that I have pain/problems with during relapses. It all seems to make sense.

I am more worried about how infectious XMRV is, since they found it in all bodily fluids.... If one tests positive how do you live without fear of passing it on with casual contact?

Frustrating. Does it seem to anyone else that all this is not headed in a helpful direction...? Less hope in discovering XMRV as a key player in CFS, and more of the same politicized discussion of it as just another pathogen (EBV, HHV6, Lyme, etc.) in the mix that might cause that bewildering CFS in people who must have susceptible genes and like to whine? Can we look forward to XMRV becoming like Lyme--politics and no medical consensus after decades?

If discussion of the monkeys if pointless (disability level was not measured in them, their ability to "clear" the virus and possibly enjoy remission seems dissimilar to most PWC, who just decline forever), and there's more useful information in the cats with FeLV, then please DISCUSS THE CATS WITH FeLV.

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I actually think it is heading in a good direction. I think the problem is that XMRV is a rather tricky; it is not found by some PCR methods that often find pathogens and then there are the 'variants' plus its very rare in the body....The key is that in contract to the other pathogens in CFS work is being done by top-notch reseachers. Lipkin is a world renowned pathogen hunter. Dr. Vernon, who apparently knows him pretty well, she called him 'Ian', said he's been interested in CFS since the 1980's when he saw CFS patients in San Francisco. He's believed CFS is the result of a viral infection since then.

He is another example of a researcher who's been waiting in the wings to have a stab at CFS when the opportunity presented itself.

Frustrating. Does it seem to anyone else that all this is not headed in a helpful direction...? Less hope in discovering XMRV as a key player in CFS, and more of the same politicized discussion of it as just another pathogen (EBV, HHV6, Lyme, etc.) in the mix that might cause that bewildering CFS in people who must have susceptible genes and like to whine? Can we look forward to XMRV becoming like Lyme--politics and no medical consensus after decades?

If discussion of the monkeys if pointless (disability level was not measured in them, their ability to "clear" the virus and possibly enjoy remission seems dissimilar to most PWC, who just decline forever), and there's more useful information in the cats with FeLV, then please DISCUSS THE CATS WITH FeLV.

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Dr. Singh announced at the 1st International XMRV conference that she was just a couple months away from publishing her cadaver study on XMRV and MLV's. During her talk on Saturday morning she went on at length about the importnace of looking closely at full sections of tissues and not just micro arrays as it is very easy to take too small a section of tissue and miss the infect cells right next door. The take home was that XMRV may be more common than we ever realized but that when it is infecting tissue (and blood), it exists in very low concentration/copy numbers. This all ties back to her comment that "we have already picked all of the low hanging fruit" suggesting that XMRV/MLV's represent a new avenue (and challenge) as our previous gold standard techniques are not in themselves adequate.